Phenylpiperazine derivatives with a combination of partial dopamine-D2 receptor agonism and serotonin reuptake inhibition

ABSTRACT

The invention relates to a group of novel phenylpiperazine derivatives with a dual mode of action: serotonin reuptake inhibition and partial agonism on dopamine-D 2  receptors. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect. 
 
The compounds have the general formula (1):  
                 
wherein the symbols have the meanings given in the specification. and tautomers, stereoisomers and N-oxides thereof, as well as pharmacologically acceptable salts, hydrates and solvates of said compounds of formula (1) and its tautomers, stereoisomers and N-oxides.

The present invention relates to a group of novel phenylpiperazinederivatives with a dual mode of action: serotonin reuptake inhibitionand partial agonism on dopamine-D₂ receptors. The invention also relatesto the use of a compound disclosed herein for the manufacture of amedicament giving a beneficial effect. A beneficial effect is disclosedherein or apparent to a person skilled in the art from the specificationand general knowledge in the art. The invention also relates to the useof a compound of the invention for the manufacture of a medicament fortreating or preventing a disease or condition. More particularly, theinvention relates to a new use for the treatment of a disease orcondition disclosed herein or apparent to a person skilled in the artfrom the specification and general knowledge in the art. In embodimentsof the invention specific compounds disclosed herein are used for themanufacture of a medicament useful in the treatment of disorders inwhich dopamine-D₂ receptors and serotonin, reuptake sites are involved,or that can be treated via manipulation of those targets.

Compounds with a dual action as dopamine-D₂ antagonists and serotoninreuptake inhibitors are known from WO 00/023441, WO 00/069424 and WO01/014330. This combination of activities is useful for the treatment ofschizophrenia and other psychotic disorders: it enables a more completetreatment of all disease symptoms (e.g. positive symptoms and negativesymptoms).

The goal of the present invention was to provide further compounds witha dual action as partial dopamine-D₂ antagonists and serotonin reuptakeinhibitors.

The invention relates to a group of novel compounds of the formula (1):

wherein:

X═S or O,

R₁ is H, (C₁-C₆)alkyl, CF₃, CH₂CF₃, OH or O—(C₁-C₆)alkyl

R₂ is H, (C₁-C₆)alkyl, halogen or cyano

R₃ is H or (C₁-C₆)alkyl

R₄ is H, (C₁-C₆)alkyl, optionally substituted with a halogen atom

-   T is a saturated or unsaturated carbon chain of 2-7 atoms, wherein    one carbon atom may be replaced with a nitrogen atom, optionally    substituted with an (C₁-C₃)alkyl, CF₃ or CH₂CF₃ group, an oxygen    atom or a sulphur atom, which chain is optionally substituted with    one or more substituents selected from the group consisting of    (C₁-C₃)alkyl, (C₁-C₃)alkoxy, halogen, cyano, trifluoromethyl, OCF₃,    SCF₃, OCHF₂ and nitro,-   Ar is selected from the groups:-   which Ar group is optionally further substituted with one or more    substituents selected from the group consisting of (C₁-C₃)alkyl,    (C₁-C₃)alkoxy, halogen, cyano, trifluoromethyl, OCF₃, SCF₃, OCHF₂    and nitro,-   and in which Ar groups that contain a five-membered ring, the double    bond in the five-membered ring may be saturated,-   and tautomers, stereoisomers and N-oxides thereof, as well as    pharmacologically acceptable salts, hydrates and solvates of said    compounds of formula (1) and its tautomers, stereoisomers and    N-oxides.

In the groups ‘Ar’, the dot represents the attachement point of group‘T’.

In the description of the substituents the abbreviation ‘alkyl(C₁₋₃)’means ‘methyl, ethyl, n-propyl or isopropyl’.

Prodrugs of the compounds mentioned above are in the scope of thepresent invention. Prodrugs are therapeutic agents which are inactiveper se, but are transformed into one or more active metabolites.Prodrugs are bioreversible derivatives of drug molecules used toovercome some barriers to the utility of the parent drug molecule. Thesebarriers include, but are not limited to, solubility, permeability,stability, presystemic metabolism and targeting limitations (MedicinalChemistry: Principles and Practice, 1994, Ed.: F. D. King, p. 215; J.Stella, “Prodrugs as therapeutics”, Expert Opin. Ther. Patents, 14(3),277-280, 2004; P. Ettmayer et al., “Lessons learned from marketed andinvestigational prodrugs”, J. Med. Chem., 47, 2393-2404, 2004).Pro-drugs, i.e. compounds which when administered to humans by any knownroute, are metabolised to compounds having formula (1), belong to theinvention. In particular this relates to compounds with primary orsecondary amino or hydroxy groups. Such compounds can be reacted withorganic acids to yield compounds having formula (1) wherein anadditional group is present which is easily removed afteradministration, for instance, but not limited to amidine, enamine, aMannich base, a hydroxyl-methylene derivative, an O-(acyloxy-methylenecarbamate) derivative, carbamate, ester, amide or enaminone.

N-oxides of the compounds mentioned above are in the scope of thepresent invention. Tertiary amines may or may not give rise to N-oxidemetabolites. The extend to what N-oxidation takes place varies fromtrace amounts to a near quantitative conversion. N-oxides may be moreactive than their corresponding tertiary amines or less active. WhilstN-oxides are easily reduced to their corresponding tertiary amines bychemical means, in the human body this happens to varying degrees. SomeN-oxides undergo nearly quantitative reductive conversion to thecorresponding tertiary amines, in other cases the conversion is a meretrace reaction or even completely absent. (M. H. Bickel: “Thepharmacology and Biochemistry of N-oxides”, Pharmaco-logical Reviews,21(4), 325-355, 1969).

It has been found that the compounds according to the invention showhigh affinity for both the dopamine D₂ receptor and the serotoninreuptake site. The compounds show activity at dopamine D₂ receptors withvarying degree of agonism. All of the compounds show activity asinhibitors of serotonin reuptake, as they potentiate 5-HTP inducedbehaviour in mice (B. L. Jacobs., ‘An animal behaviour model forstudying central serotonergic synapses’; Life Sci., 1976, 19(6)777-785).

In contrast to the use of full dopamine-D₂ receptor agonists orantagonists, the use of partial dopamine-D₂ receptor agonists offers adynamic medication that self-adjusts on a moment-to-moment basis to theendogenous state of the patient. Thus, it provides the desired flexiblemodulation of the dopamine system and avoidance of the many adverseeffects caused either by treatment using full dopamine-D₂ receptoragonists like bromocriptine (hallucinations, nausea, vomiting,dyskinesia, orthostatic hypotension, somnolescence) or full dopamine-D₂receptor antagonists like haloperidol (emotional blunting, dysphoria,tardive dyskinesia). Because of these many adverse effects, fullagonists and antagonists have found only very limited use in the therapyof depressive and anxiety disorders. Partial dopamine-D₂ receptoragonists not only show a flexible modulation and a favourableside-effect profile, they also have a pronounced anxiolytic profile inrelevant animal models (Drugs of the Future 2001, 26(2): 128-132).

Partial dopamine-D₂ receptor agonists, according to the presentinvention, are compounds that—when tested in a concentration responserange—achieve activation in the functional cAMP cell based assay (asdescribed below). Partial dopamine-D₂ receptor agonists will act as anagonist in cases when the endogenous synaptic tone of dopamine is low,or in the the presence of a full dopamine-D₂ receptor antagonist, andwill act as an antagonist in cases when the endogenous synaptic tone ofdopamine is high, or in the presence of a full dopamine D₂ receptoragonist. Like full agonists, partial dopamine-D₂ receptor agonists ingeneral are active in sensitized systems. They induce contralateralturning in rats with unilateral 6-hydroxy-dopamine (6-OHDA) lesions inthe substantia nigra pars compacta. In MPTP-treated common marmosetsthey produce potent and long-lasting reversal of motor symptoms (Drugsof the Future 2001, 26(2): 128-132). In contrast to full agonists,however, partial dopamine-D₂ agonists are substantially less active innon-sensitized systems: they hardly reverse reserpine inducedhypolocomotion in rats.

For the treatment of CNS disorders involving an overactive dopaminergicsystem a pharmaceutical preparation combining partial dopamine-D₂receptor agonistic activity having low intrinsic functional activitywith serotonin reuptake inhibitory activity is recommended. In case of adisorder involving dopamine insufficiency a pharmaceutical preparationcombining partial dopamine-D₂ receptor agonistic activity with highintrinsic functional activity and serotonin reuptake activity accordingto the invention has considerable advantages.

Disorders characterized by dynamic fluctuations in dopamineneurotransmission like bipolar depression and addiction will profit inparticular from the flexible adjustment of the dopamine system by thepartial dopamine-D₂ receptor agonists in the pharmaceutical preparation.Combining this “dopaminergic neurotransmission stabilizing” activitywith serotonin reuptake inhibitory activity will enhance antidepressiveand anxiolytic efficacy. The compounds can be used for the treatment ofaffections or diseases of the central nervous system caused bydisturbances in the dopaminergic and serotonergic systems, for example:aggression, anxiety, disorders, autism, vertigo, depression,disturbances of cognition or memory, Parkinson's disease, and inparticular schizophrenia and other psychotic disorders.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by mixing a compound ofthe present invention with a suitable acid, for instance an inorganicacid such as hydrochloric acid, or with an organic acid.

Pharmaceutical Preparations

The compounds of the invention can be brought into forms suitable foradministration by means of usual processes using auxiliary substancessuch as liquid or solid carrier material. The pharmaceuticalcompositions of the invention may be administered enterally, orally,parenterally (intramuscularly or intravenously), rectally or locally(topically). They can be administered in the form of solutions, powders,tablets, capsules (including microcapsules), ointments (creams or gel)or suppositories. Suitable excipients for such formulations are thepharmaceutically customary liquid or solid fillers and extenders,solvents, emulsifiers, lubricants, flavorings, colorings and/or buffersubstances. Frequently used auxiliary substances which may be mentionedare magnesium carbonate, titanium dioxide, lactose, mannitol and othersugars, talc, lactoprotein, gelatin, starch, cellulose and itsderivatives, animal and vegetable oils such as fish liver oil,sunflower, groundnut or sesame oil, polyethylene glycol and solventssuch as, for example, sterile water and mono- or polyhydric alcoholssuch as glycerol.

Compounds of the present invention are generally administered aspharmaceutical compositions which are important and novel embodiments ofthe invention because of the presence of the compounds, moreparticularly specific compounds disclosed herein. Types ofpharmaceutical compositions that may be used include but are not limitedto tablets, chewable tablets; capsules, solutions, parenteral solutions,suppositories, suspensions, and other types disclosed herein or apparentto a person skilled in the art from the specification and generalknowledge in the art. In embodiments of the invention, a pharmaceuticalpack or kit is provided comprising one or more containers filled withone or more of the ingredients of a pharmaceutical composition of theinvention. Associated with such container(s) can be various writtenmaterials such as instructions for use, or a notice in the formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals products, which notice reflects approval by theagency of manufacture, use, or sale for human or veterinaryadministration.

Pharmacological Methods

In Vitro Affinity for Dopamine-D₂ Receptors

Affinity of the compounds for dopamine-D₂ receptors was determined usingthe receptor binding assay described by 1. Creese, R. Schneider and S.H. Snyder: “[³H]-Spiroperidol labels dopamine receptors in rat pituitaryand brain”, Eur. J. Pharmacol., 46, 377-381, 1977.

In Vitro Affinity for Serotonin Reuptake Sites

Affinity of the compounds for serotonin reuptake sites was determinedusing the receptor binding assay described by E. Habert et al.,:“Characterisation of [³H]-paroxetine binding to rat cortical membranes”,Eur. J. Pharmacol., 118, 107-114, 1985.

Inhibition of Forskolin-Induced [³H]-cAMP Accumulation

The in vitro functional activity at dopamine-D₂ receptors, including theintrinsic activity (E) of the compounds of the invention was measured bytheir ability to inhibit forskolin-induced [³H]-cAMP accumulation.

Human dopamine D_(2,L) receptors were cloned in fibroblast cell lineCHO-K1′ cells and obtained from Dr. Grandy, Vollum Institute, Portland,Oreg., USA. CHO cells were grown in a Dulbecco's modified Eagle's medium(DMEM) culture medium, supplemented with 10% heat-inactivated fetal calfserum, 2 mM glutamine, 1 mM pyruvate, 5000 units/ml penicillin, 5000μg/ml streptomycin and 200 μg/ml G-418 at 37° C. in 93% air/7% CO₂. Forincubation with test compounds, confluent cultures grown in 24 wellsplates were used. Each condition or substance was routinely tested inquadruplicate. Cells were loaded with 1 μCi [³H]-adenine in 0.5 mlmedium/well. After 2 hours, cultures were washed with 0.5 ml PBScontaining 1 mM of the phosphodiesterase inhibitorisobutylmethylxanthine (IBMX) and incubated for 20 min with 0.5 ml PBScontaining 1 mM IBMX and forskolin with or without test compound. Afteraspiration the reaction was stopped with 1 ml trichloroacetic acid 5%(w/v). The [³H]-ATP and [³H]-cAMP formed in the cellular extract wereassayed as described by Solomon Y, Landos C, Rodbell M, 1974, A highlyselective adenylyl cyclase assay, Anal Biochem 58:541-548 and Weiss S,Sebben M, Bockaert J J, 1985, Corticotropin-peptide regulation ofintracellular cyclic AMP production in cortical neurons in primaryculture, J Neurochem 45:869-874. 0.8 ml Extract was passed over Dowex(50WX-4 200-400 mesh) and aluminumoxide columns, eluted with water and0.1M imidazole (pH=7.5). Eluates were mixed with 7 ml Insta-gel andradioactivity was counted with a liquid scintillation counter. Theconversion of [³H]-ATP into [³H]-cAMP was expressed as the ratio inpercentage radioactivity in the cAMP fraction as compared to combinedradioactivity in both cAMP and ATP fractions, and basal activity wassubtracted to correct for spontaneous activity.

Test compounds were obtained as 10 mM stock solutions in 100% DMSO, anddiluted in PBS/IBMX to final concentrations. Typically, compounds wereused in concentrations that ranged from 10⁻¹⁰M to 10⁻⁵M. Fromquadruplicate data counts, the mean was taken as an estimate fordrug-induced, receptor-mediated effects at specified second messengeraccumulation, expressed as percentage of control values(forskolin-stimulated cAMP accumulation, subtracted by basal activity).By using the non-linear curve-fitting program INPLOT or the Excel-add-inXL-Fit, mean values were plotted against drug concentration (in molar)and a sigmoid curve (four-parameter logistic curve) was constructed. Themaximal forskolin-induced stimulated conversion is taken as maximumvalue and the maximal inhibition (usually at drug concentrations 10⁻⁴ Mor 10⁻⁵ M) as minimum and these values were fixed during the fittingprocess. Thus, concentrations of the compound, causing 50% of themaximally obtained inhibition of forskolin-induced cAMP accumulation(EC₅₀), are averaged over several experiments and presented as meanpEC₅₀±SEM. Antagonist potency is assessed by co-incubating cells with afixed agonist concentration and specified antagonist concentrations.Curve fitting procedures are identical to those used for estimating EC₅₀values. Thus IC₅₀ values, i.e. the concentration that is able to achieve50% of maximal antagonism that can be achieved by this compound. IC₅₀values are corrected using a Cheng-Prussoff equation, correcting it foragonist concentration and EC₅₀ values that is obtained in the sameexperiment. Thus, K_(b)=IC₅₀/(1+[agonist]/EC₅₀, agonist). Thecorresponding pA₂ value is −log (K_(b)). Concentration-response curvefitting allows estimation of pEC₅₀ values and of maximal achievableeffect (intrinsic activity or efficacy (ε). A full receptor agonist hasε=1, a full receptor antagonist has ε=0, and a partial receptor agonisthas an intermediate intrinsic activity.

Dosages

The affinity of the compounds of the invention for dopamine-D₂ receptorsand serotonine reuptake sites was determined as described above. Fromthe binding affinity measured for a given compound of formula (1), onecan estimate a theoretical lowest effective dose. At a concentration ofthe compound equal to twice the measured K_(i)-value, 100% of thereceptors likely will be occupied by the compound. Converting thatconcentration to mg of compound per kg of patient yields a theoreticallowest effective dose, assuming ideal bioavailability. Pharmacokinetic,pharmacodynamic, and other considerations may alter the dose actuallyadministered to a higher or lower value. The dosage expedientlyadministered is 0.001-1000 mg/kg, preferably 0.1-100 mg/kg of patient'sbodyweight.

Treatment

The term ‘treatment’ as used herein refers to any treatment of amammalian, preferably human condition or disease, and includes: (1)preventing the disease or condition from occurring in a subject whichmay be predisposed to the disease but has not yet been diagnosed ashaving it, (2) inhibiting the disease or condition, i.e., arresting itsdevelopment, (3) relieving the disease or condition, i.e., causingregression of the condition, or (4) relieving the conditions caused bythe disease, i.e., stopping the symptoms of the disease.

Materials and Methods

¹H and ¹³C NMR spectra were recorded on a Bruker Avance DRX600instrument (600 MHz), Varian UN400 instrument (400 MHz) or on a VarianVXR200 instrument (200 MHz) using DMSO-D₆ or CDCl₃ as solvents withtetramethylsilane as an internal standard. Chemical shifts are given inppm (δ scale) downfield from tetramethylsilane. Peakshapes in the NMRspectra are indicated with the symbols ‘q’ (quartet), ‘dq’ (doublequartet), ‘t’ (triplet), ‘dt’ (double triplet), ‘d’ (doublet), ‘dd’(double doublet), ‘s’ (singlet), ‘bs’ (broad singlet) and ‘m’(multiplet). Flash chromatography was performed using silica gel 60(0.040-0.063 mm, Merck). Column chromatography was performed usingsilica gel 60 (0.063-0.200 mm, Merck). Mass spectra were recorded on aMicromass QTOF-2 instrument with MassLynx application software foracquisition and reconstruction of the data. Exact mass measurement wasdone of the quasimolecular ion [M+H]⁺. Melting points were recorded on aBuchi B-545 melting point apparatus.

Yields refer to isolated pure products. The preparation of the compoundshaving formula (I) will now be described in more detail in the followingExamples.

EXAMPLES

The H-atom of the N-H moiety of amines I-H to X-H can be replaced by Qin two different chemical ways, A and B, eventually leading to thecompounds of the invention which are listed in table 1 (see below.

Method A:

The compounds were prepared via the synthesis depicted in scheme A1: anamine (from FIG. 1) was reacted with Q-X (X=leaving group like e.g. Cl,Br, I) in e.g. acetonitrile or butyronitrile with Et(i-Pr)₂N acting as abase, in some cases KI (or NaI) was added. Et₃N ran be used instead ofEt(i-Pr)₂N.

Example 1

Scheme A2, Step i: To a suspension of 0.6 g (2.35 mmol) of thepiperazine hydrochloride I-H.HCl in 100 ml of acetonitril were added0.77 g (2.35 mmol) of the iodide, 0.71 g (4.7 mmol) of NaI and 1.39 ml(8 mmol) of DIPEA. The mixture was refluxed for 20 hours andconcentrated in vacuo. The residue was taken up in CH₂Cl₂ and theresulting mixture washed with water. The organic layer was dried onNa₂SO₄. The drying agent was removed by filtration and the solvent byconcentration in vacuo.

The residue was purified by flash column chromatography (SiO₂, eluentCH₂Cl₂/MeOH/NH₄OH 960/37.5/2.5). The product containg fractions wereconcentrated in vacuo leaving a residue which was stirred indiisopropylether. The solid material was collected by filtration,yielding 0.79 g (81%) of compound 9. M.p.: 228-230° C.

Method B:

The compounds were prepared via the synthesis depicted in scheme B1: anamine (from FIG. 1) was alkylated by means of a reductive alkylation.Q-OH was oxidized to the corresponding aldehyde Q′-CHO after whichreductive alkylation was performed. THF and DCE are suitable solventsfor this type of reaction.

Example 2

The Swern oxidation was carried out according to literature: Anthony J.Mancuso, Daniel Swern; Synthesis, (1981) 165-184.

Scheme B2, Step i:

A solution of oxalyl chloride (0.45 ml, 5.2 mmol) in 15 ml DCM is placedin a three-necked round bottom flask equipped with a thermometer and twopressure-equalizing dropping funnels respectively containing dimethylsulfoxide (0.74 ml, 10.4 mmol) in 3 ml DCM, and the3-(6-chloro-indazo-1-yl)-propanol Q56-OH (1.0 g, 4.7 mmol) in 5 ml DCMunder an N₂ atmosphere. The dimethyl sulfoxide is added to the stirredoxalyl chloride solution at −50° C. to −60° C. The reaction mixture isstirred for 2 minutes and the alcohol is added within 5 minutes;stirring is continued for an additional 15 minutes. Triethylamine (3.3ml, 23.73 mmol) is added and the reaction mixture is stirred for 15minutes and then allowed to warm to room temperature. Water is added andthe aqueous layer is re-extracted with additional DCM. The organic layeris washed with 0.3 N HCl, water, 5% NaHCO₃, saturated NaCl solution anddried with Na₂SO₄. The filtered solution is evaporated yielding thecorresponding aldehyde.

Scheme B2, Step ii:

The crude product containing the aldehyde (from step i) is added to astirred solution of 3-7-piperazin-1-yl-3H-benzooxazole-2-one.2HCl(V.2HCl) (0.57 g, 2.44 mmol) and tri-ethyl amine (0.76 ml, 5.38 mmol) in100 ml DCE. The reaction mixture is stirred for 1 hour and NaBH(OAc)₃(0.83 g, 3.91 mmol) is added. The mixture is stirred for an additional 8hours. Water was added and the resulting fraction extracted with DCM (3times). The combined organic layers were evaporated. The crude productwas purified by flash chromatography on silica (eluent: 1.5% MeOH inDCM→2% MeOH in DCM) to afford 128 as a crystalline solid in a 58% yield.Melting point: 118-120° C. TABLE 1 examples of compounds of theinvention. Comp. L- melting nr. amine Q meth. group salt r. ° C. 1 I 1 AI free base   194-196.5 2 I 2 A I free base 168-170 3 I 3 A I free base206.5-207.5 4 I 4 A I free base 173.5-175   5 I 5 A I free base 173-1766 I 6 A I free base 180-182 7 I 7 A I free base 211-213 8 I 8 A I freebase 193-195 9 I 9 A I free base 228-230 10 I 10 A I free base 186-18811 I 11 A I free base 176-178 12 I 12 A I free base 212-214 13 I 13 A Ifree base 183-184 14 I 14 A I HCl 225-227 15 I 15 A I HCl 255-260 16 I16 A I free base 143-145 17 I 17 A I free base 152-157 18 I 18 A I freebase 157-159 19 I 19 A I HCl 179-181 20 I 20 A I free base 174.5-177  21 I 21 A Cl free base 180-183 22 I 22 A I free base 206-208 23 I 23 A Ifree base 202-204 24 I 25 A I free base 154-156 25 I 29 A I free baseamorph 26 I 30 A I free base 177-179 27 I 31 A I free base 153-156 28 I32 A I free base 174-177 29 I 33 A Br free base 187-190 30 I 34 A Brfree base 190-192 31 I 35 A Br free base 174-177 32 I 36 A Br free base198-200 33 I 37 A Br free base 194-195 34 I 38 A Br free base 137-138 35I 39 A Br free base 136-138 36 I 40 A Cl free base 121-123 37 I 41 A Brfree base 133-135 38 I 42 A Br free base 135-137 39 I 43 A Cl free base111-112 40 I 44 B free base 200-202 41 I 45 A Br free base 197-199 42 I46 A Cl free base 162-164 43 I 47 A Br free base 204-206 44 I 48 A Clfree base 162-164 45 I 49 A Br free base 188-189 46 I 50 A Cl free base146-149 47 I 51 A Cl free base 109-113 48 I 52 A Br free base  75-105amorph 49 I 53 A Br free base 209-210 50 I 54 B free base 201-203 51 I55 B free base 161-162 52 I 56 B free base 203-204 53 I 57 B free base83-86 54 I 58 B free base 172-174 55 I 59 B free base 134-137 56 I 60 ABr free base 214-6  57 I 61 A I HCl 214-6  58 I 62 A I HCl  275-7 (d) 59I 63 A I free base NMR** 60 I 64 A Cl free base 234-6  61 II 3 A I freebase 187-189 62 II 5 A I free base 157-159 63 II 6 A I free base 154-15664 II 8 A I free base 190-192 65 II 9 A I free base 234-236 66 II 11 A Ifree base 176-178 67 II 13 A I free base 236-239 68 II 15 A I free base156-158 69 II 16 A I HCl 256-260 70 II 17 A I HCl 244-246 71 II 26 A IHCl  232-5 (d) 72 II 29 A I free base 157-158 73 II 31 A I free base190-1  74 II 32 A I free base 168-170 75 II 35 A Br free base 170-173 76II 36 A Br free base 193-196 77 II 45 A Br free base 166-169 78 II 47 ABr free base 108-113 79 II 49 A Br free base 168-170 80 II 50 A Cl freebase 194-7  81 II 59 B free base 153-5  82 II 61 A I free base 157-9  83III 16 A I free base 153-154 84 IV 16 A I free base 163-5  85 V 1 A Ifree base 125-127 86 V 3 A I free base 153-155 87 V 4 A I HCl 182-183 88V 5 A I free base 113-116 89 V 6 A I free base 162-164 90 V 8 A I freebase 119-121 91 V 9 A I free base 150-152 92 V 10 A I free base 141-14293 V 11 A I free base 124-126 94 V 12 A I free base 184-186 95 V 13 A IHCl 107 96 V 14 A I HCl 197-199 97 V 15 A I HCl 216-218 98 V 16 A I HCl199-201 99 V 17 A I HCl 214-218 100 V 18 A I free base 228-229 101 V 19A I free base 132-134 102 V 20 A I free base 138-140 103 V 22 A I freebase 143-145 104 V 23 A I free base 150-152 105 V 24 A I free base179-181 106 V 25 A I HCl 197-199 107 V 26 A I free base 105-107 108 V 28A I free base 146-147 109 V 31 A I free base 119-21 110 V 33 A Br HCl >240 d 111 V 34 A Br free base 108-111 112 V 35 A Br free base 129-132113 V 36 A Br HCl  >240 d 114 V 37 A Br free base 146-149 115 V 41 A Brfree base 117-118 116 V 42 A Br free base 110-112 117 V 43 A Cl freebase 167-170 118 V 45 A Br free base 111-113 119 V 46 A Cl free base88-91 120 V 47 A Br free base 131-133 121 V 49 A Br free base 124-126122 V 50 A Cl free base 103-105 123 V 51 A Cl free base 112-115 124 V 52A Br free base 203-205 125 V 53 A Br HCl 262-264 126 V 54 B free base116-118 127 V 55 B free base 104-107 128 V 56 B free base 118-120 129 V57 A I free base 108-112 130 V 58 B free base 102-104 131 V 59 B freebase 125-128 132 V 60 A Br free base 202-3  133 V 61 A I HCl 194-7  134V 62 A I HCl  274-6 (d) 135 V 63 A I free base NMR** 136 V 64 A Cl freebase 154-5  137 VI 16 A I free base 134-6  138 VI 31 A I free base125-6  139 VI 50 A Cl free base 116-8  140 VI 59 B free base 130-2  141VII 16 A I HCl 274-276 142 VIII 16 A I free base 135-137 143 IX 3 A Ifree base 106-108 144 IX 6 A I free base 117-119 145 IX 49 A Br HCl204-206 146 IX 50 A Cl free base 107-109NMR**, compound 59: (d, ppm) 3.36 (t, broad, Ph—N(CH ₂CH₂)₂N—)NMR**, compound 135: (d, ppm) 3.29 (t, broad, Ph—N(CH ₂CH₂)₂N—)**CDCl₃/d⁶-DMSO = ¼

Structures of the phehylpiperazine part of the compounds of formula (1),herein termed ‘amines’, and groups ‘Q’ are given below. In the column‘method’, the general method (A or B) is given, and in case of method A,the next column gives the leaving group.

The phenylpiperazine parts of the compounds of formula (1) used in thesemethods are indicated as I-H to IX-H, wherein the dot on the N-atom isthe attachment point for the group Q:

The syntheses of the piperazines I-H, III-H and V-H are described inWO97/36893.Synthesis of Amine II-H:

The synthesis of the starting material has been described (patentDE487014).

Scheme II, Step i:

30 g ((0.14 mol) of the starting material was suspended in 600 ml ofMeOH. Then a small amount of Raney nickel was added after whichhydrogenation was started (atmospheric, room temperature). After 24hours 7.2 liters (theoretical amount 9.4 liters) of hydrogen wasabsorbed. To the reaction mixture 150 ml of THF was added and anothersmall amount of Raney nickel. After one hour the reaction mixture wasfiltered over hyflo, the residue washed with THF. The filtrate wasconcentrated in vacuo, yielding 25.2 g (98%) of the correspondiganiline.

Scheme II, Step ii:

24.2 g (131.2 mmol) of the aniline of the previous step and 25.8 g(144.3 mmol) of bis (2-chloroethyl)amine were suspended in 675 ml ofchlorobenzene. While stirring, 25 ml of solvent were distilled off withthe aid of a Dean-Stark apparatus. After removal of the Dean-Starkapparatus, the reaction was allowed to reflux for 48 hours. When thereaction mixture had come to room temperature, the mixture was decantedand the residue washed twice with Et₂O. Then 400 ml of MeOH were addedafter which the mixture was warmed until almost all of the residue wasdissolved. Then 200 ml of silica were added after which the whole wasconcentrated in vacuo. Then the residue was put on top of a flashchromatography column using DMA 0.75 as the eluent. After removal of thesolvent a residue was isolated which was suspended in about 100 ml ofacetonitrile and stirred for 4 hours. Filtration and drying yielded 17 gof the desired piperazine II-H as a free base.Synthesis of Amine IV-H:

The toluene used in this experiment was degassed for three hours priorto usage. 1.48 g (1.61 mmol) of Pd₂(dba)₃ and 3.02 g (4.85 mmol) ofBINAP were put into 400 ml of toluene after which the mixture wasstirred and heated to 105° C. for 0.5 hours after which the mixture wasallowed to room temperature. Subsequently were added to the reactionmixture: 27.

Scheme IV, Step i:

20.5 g (81.3 mmol) of dibromophenol and 20 g of potassium carbonate weresuspended in 400 ml of aceton, after which 15.7 ml of benzylbromide wereadded. The reaction mixture was refluxed for 24 hours. After the mixturehad reached room temperature, it was concentrated in vacuo. Subsequentlywater was added and CH₂Cl₂. The organic layer was filtered with a waterrepellant filter, the dry filtrate concentrated in vacuo after which itwas dissolved again in 200 ml of acetonitrile. Subsequently, 15 ml ofpiperidine were added after which the temperature was raised to 60° C.for one hour. The reaction mixture was concentrated in vacuo and CH₂Cl₂was added. The latter was washed with: 1N HCl (3×), water, 2N NaOH, andagain water. The organic layer was filtered with a water repellantfilter, the dry filtrate concentrated in vacuo yielding 27.6 g (99%) ofthe corresponding benzylated phenol.

Scheme IV, Step ii:

6 g (80.7 mmol) of the benzylated compound (step i) dissolved in 50 mlof toluene, 9.2 g (80.7 mmol) of the (α,α′)-dimethylpiperazine and 10.08g (104.9 mmol) of sodium tertbutoxide. The resulting mixture was heatedat 105° C. for 20 hours, after which it was allowed to reach roomtemperature. The mixture was diluted with CH₂Cl₂ after which it wasfiltered over hyflo and concentrated in vacuo. The residue was put ontop of a flash chromatography column (SiO₂) using DMA 0.125. Thecombined product containing fractions yielded after concentration invacuo 7.7 g (26%) of the almost pure phenylpiperazine.

Scheme IV, Step iii:

This step was done analogously to the procedure described in theprevious step ii (scheme IV). In this case benzylamine was used in theBuchwald reaction. Yield: 88%.

Scheme IV, Step iv:

7 ml (98 mmol) of acetyl chloride was added dropwise to 70 ml of cooledabsolute ethanol, stirring was continued for 15 minutes. The lattersolution was added to a solution of 11.5 g (28.7 mmol) of the dibenzylproduct of step iii in 250 ml of methanol. Subsequently 1.5 g of Pd/C(10%) was added, after which the reaction mixture was hydrogenated for24 hours. The mixture was filtered over hyflo, the filtrate concentratedin vacuo. The residue containing the amino phenol HCl salt was directlyused in step v.

Scheme IV Step v:

The residue (28.7 mmol) obtained in step iv, 52 ml of DIPEA (298 mmol),and 20.9 g (129 mmol) of CDI were added to 750 ml of THF after which themixture was refluxed for 20 hours under a nitrogen atmosphere. Aftercooling to room temperature, the mixture was concentrated in vacuo, tothe residue CH₂Cl₂ and 5% NaHCO₃ were added, the whole being stirred forone hour. Extraction with CH₂Cl₂ (3×), the water fraction wasconcentrated and extracted again (CH₂Cl₂, 3×). The combined organicfractions were concentrated in vacuo, the residue contained aconsiderable amount of imidazol. The whole was solved in 120 ml ofacetonitrile after which the solution was allowed to reach roomtemperature. The precipitate which formed was filtered yielding almostpure piperazine IV.Synthesis of Amine V-H:

Scheme V, Steps i, ii and iii:

Synthesis of V-H has been described in WO97/36893. The steps i, ii andiii were done analogously to steps i, ii and iii in scheme VI.Synthesis of Amine VI-H:

Scheme VI, Step i:

While stirring, 3.8 g (15 mmol) of piperazine II-H were suspended in5.48 ml (31.5 mmol) of DIPEA and the mixture was brought to −40° C. Asolution of 3.14 g (14.4 mmol, 0.96 eq) of Boc-anhydride in 30 ml ofCH₂Cl₂ was added dropwise in 100 minutes. Stirring was continued at −40°C. (1 hour), then at −30° C. (2 hours), and the reaction mixture wasallowed to come to room temperature (16 hours). Then water and some MeOHwere added after which it was extracted with CH₂Cl₂. The combinedorganic fractions were filtered with a water repellant filter, the dryfiltrate mixed with 50 ml of silica after which the whole wasconcentrated in vacuo. Then the residue was put on top of a drychromatography column (SiO₂) using CH₂Cl₂/MeOH (98/2) as the eluent. Thepart of the column containing the product was cut out, and the productwashed out of the column material with CH₂Cl₂/MeOH (98/2) yielding 3.55g (67%) of the desired N-Boc II.

Scheme VI, Step ii:

4.5 g (12.7 mmol) N-Boc II together with 5.8 g (3.3 eq) of potassiumcarbonate were suspended in 100 ml of aceton. While stirring, thereaction mixture was cooled to −10° C. after which 0.87 ml (14 mmol, 1.1eq) of methyl iodide was added dropwise. After 15 minutes, the reactionmixture was allowed to reach room temperature and stirring was continuedfor 14 hours. Subsequently, the reaction mixture was concentrated invacuo, the residue mixed with water and CH₂Cl₂. The water layer wasseparated and extracted twice with CH₂Cl₂. The combined organic layerswere filtered with a water repellant filter, the dry filtrateconcentrated in vacuo yielding 4.5 g (98%) of the correspondingN′-methylated N-Boc II.

Scheme VI, Step iii:

While stirring at −10° C., 5 ml of acetyl chloride (70.4 mmol, 5.8 eq)was added dropwise to 65 ml of ethanol. The latter solution was added to4.5 g (12.2 mmol) of the N′-methylated N-Boc II isolated in step ii. Theresulting mixture was stirred for 3 hours at 55° C., then the reactionmixture was allowed to reach room temperature and stirring was continuedfor 14 hours. Subsequently, the mixture was concentrated in vacuo afterwhich the residue was suspended in di-isopropyl ether and stirred for 2hours. The precipitate was isolated by filtration yielding 3.6 g (97%)of piperazine VI-H.HCl.Synthesis of Amine VII-H:

Scheme VII, Step i:

This step was done analogously to step i in scheme IV. Afterchromatograhic purification an oil containing the benzylated product,was isolated in 88% yield. The oil solidified upon standing.

Scheme VII, Step ii:

This step was done analogously to step ii in scheme IV. Boc-piperazinewas used in this Buchwald reaction. Yield after chromatographicpurification: 44% of a brown oil.

Scheme VII, Step iii:

This step was done analogously to the procedure described in theprevious step ii (scheme VII). In this case benzylamine was used in theBuchwald reaction. Yield after chromatographic purification: 73% of abrown oil.

Scheme VII, Step iv:

11.91 g (24.3 mmol) of the dibenzylated product isolated in previousstep iii (scheme, VII) was suspended in a mixture of 110 ml of ethanol,72 ml of water and 11 ml of acetic acid. While stirring, 0.5 g ofPd(OH)₂/C was added and hydrogenation was started for 6 days. After oneday and after 3 days an additional small amount of Pd(OH)₂/C was added.The reaction mixture was filtered over hyflo, the filtrate concentratedin vacuo. The residue was treated with toluene and concentrated invacuo, this procedure was repeated, leaving a dark sirup 7.9 g (88%),containing the amino phenol.

Scheme VII, Step v:

This step (ring closure with CDI) was done analogously to step v inscheme IV. The crude product after work up was chromatographed (flashcolumn, SiO₂, eluent DCM/MeOH 97/3) yielding 7.6 g of an impure brownfoam. A second chromatography (flash column, SiO₂, eluentEtOAc/petroleum ether 1/2) yielded 3.3 g (42%) of pure brown foam,containing the N-Boc protected benzoxazolinone piperazine.

Scheme VII, Step vi:

This methylation step was done analogously to the procedure described instep ii (scheme VI). Yield: 98% of a brown foam of 97% purity.

Scheme VII, Step vii:

This deprotection step was done analogously to the procedure describedin step iii (scheme VI). Yield: 94% of a light pink solid of 98% purity,containing the product VII-H.HCl.Synthesis of Amine VIII-H:

Scheme VIII, Step i:

The starting material synthesis has been described in EP0189612.

4.91 g (32.7 mmol) of the anilin was suspended in 75 ml of 48% ofHBr/water, while it was cooled to −5° C. Subsequently 2.27 g (33 mmol)of sodium nitrite dissolved in 4 ml of water, were added dropwise during15 minutes. Stirring was continued at 0° C. for 15 minutes.

Subsequently, the reaction mixture was added, in one time, to a 0° C.solution of 2.42 g (16.9 mmol) CuBr in 20 ml of 48% HBr/water. After 30minutes the reaction mixture was heated to 85° C. for one hour, afterwhich it was allowed to reach room temperature, stirring was continuedfor 14 hours. To the mixture diethyl ether and water were added, aftershaking the organic layer was isolated which was washed with water. Theorganic layer, together with some silica, was concentrated in vacuo, andthe residue was put on top of a flash chromatography column (SiO₂) usingEt₂O/petroleum ether (1/1), and later on pure Et₂O as the eluent. Thecombined product containing fractions yielded after concentration invacuo 3.3 g (47%) of the desired corresponding bromo product.

Scheme VIII, Step ii:

This step was carried out identical to step ii in scheme VI. Yield: 92%of the corresponding methylated bromo compound.

Scheme VIII, Step iii:

In the following order 6.82 g (29.9 mmol) of the methylated bromocompound, 4.03 g (35.9 mmol) of the dimethyl piperazine, 13.6 g (41.9mmol) of Cs₂CO₃, 1.42 g (2.99 mmol) of X-Phos (see Huang et al., J. Am.Chem. Soc., 125(2003)6653). and 0.55 g (0.6 mmol) of Pd₂(dba)₃ wereadded to 225 ml of toluene which was degassed for 4 hours prior tousage. While stirring and under a nitrogen atmosphere the temperaturewas raised to 100° C. for 20 hours, after which it was allowed to reachroom temperature. The mixture was diluted with CH₂Cl₂ after which it wasfiltered and concentrated in vacuo. The residue was put on top of aflash chromatography column (SiO₂) using DMA 0.25. The combined productcontaining fractions yielded after concentration in vacuo 0.73 g (9%) ofthe desired pure piperazine VIII-H.Synthesis of Amine IX-H:

Scheme IX, Steps i, ii and iii:

Synthesis of I-H has been described in WO97/36893. The steps i, ii andiii were done analogously to steps i, ii and iii in scheme VI.

Below, the different structures of Q1 to Q64 are given:

In these formulae ‘Q’, the dot represents the attachment to thephenylpiperazine part of the compounds of formula (1).Synthesis of Q1-6:

All starting materials (phenols and alkynes) were prepared according toprocedures described in the literature:

Alkynes: Davison, Edwin C.; Fox, Martin E.; J. Chem. Soc. Perkin Trans.1; 12(2002). 1494-1514. Yu, Ming; Alonso-Alicia, M.; Bioorg. Med. Chem.;11 (2003)2802-2822. Phenols: Buchan; McCombie; J. Chem. Soc.; 137 (1931)144. Finger et al; J. Amer. Chem. Soc.; 81 (1959) 94, 95, 97. Berg;Newbery; J. Chem. Soc.; (1949) 642-645.

Scheme 1-6, Step i:

R═CN, n=2

A stirred solution of the silylated alcohol (3.35 g, 10 mmol) in 20 mlof dry THF was cooled to −70° C. 2.5M n-BuLi (4.8 ml, 12 mmol) wasslowly added dropwise at such a rate that the temperature was kept below−65° C. The solution was allowed to warm to −20° C. and stirring wascontinued for 1 hour during which the color of the solution changed fromlight to dark yellow. The solution is again cooled to −70° C. and asolution of tert-butyldimethylsilylchloride (1.66 g, 11 mmol) in 15 mlof dry THF is slowly added dropwise in 10 minutes. The reaction mixturewas allowed to warm to room temperature and stirring was continued for20 h. The reaction mixture was quenched by the addition of saturatedNH₄Cl and extracted 2× with Et₂O. The combined Et₂O layers were washedwith 5% NaHCO₃ (1×) and H₂O (1×) and dried (Na₂SO₄). The Et₂O fractionwas concentrated under reduced pressure and the residue waschromatographed (SiO₂) using DMA/petroleum ether 1/5 as eluent to give3.35 g (75%) of the silylated alkyne as a colorless oil.

Scheme 1-6, Step ii:

A mixture of 4-cyano-2-iodophenol (1.23 g, 5 mmol), silylated alkyne(from step i) (2.18 g, 5 mmol), LiCl (0.21 g, 5 mmol) and Na₂CO₃ (2.38g, 22.5 mmol) in 20 ml DMF was degassed by bubbling nitrogen through thesolution for 2 h. Pd(OAc)₂ (50 mg, 0.20 mmol) was added and the reactionmixture was stirred for 7 hours at 100° C. H₂O and hexane were added andthe mixture was filtered over hyflo. After separation of the hexanelayer, the aqueous layer was extracted with hexane (1×). The combinedhexane layers were washed with H₂O (1×) and brine 1×). The hexanefraction was partially evaporated under reduced pressure and 8 g ofsilicagel was added and stirring was continued for 15 minutes. Thesilica is filtered off and the filtrate is concentrated under reducedpressure. The residue was chromatographed (SiO₂) using Et₂O/petroleumether 1/9 as the eluent to give 0.93 g (35%) of the benzfuranederivative as a light yellow oil.

Scheme 1-6, Step iii:

A mixture of the cyclized compound (29.58 g, 52.17 mmol), KF.2H₂O (14.73g, 156.51 mmol), benzyltriethylammoniumchloride (14.26 g, 62.60 mmol) in450 ml of CH₃CN was refluxed for 4 h. After cooling to room temperature,CH₃CN was washed 2× with hexane. The CH₃CN fraction was evaporated underreduced pressure. H₂O was added the residue and this was extracted twicewith EtOAc. The combined organic layers were washed with respectivelyH₂O (1×) and brine (1×). The organic layer was dried (Na₂SO₄) andconcentrated in vacuo. The residue was subjected to columnchromatography (SiO2, eluent: EtOAc/petroleum ether 1:3→EtOAc/petroleumether 1:1) to yield 9.20 g (82%) of the alcohol Q3-OH as a yellow oil.

Scheme 1-6, Step iv:

PPh₃ (14.38 g, 54.84 mmol) and imidazole (3.73 g, 54.84 mmol) weredissolved in 160 ml of CH₂Cl₂. Iodine (13.92 g, 54.84 mmol) was addedand the resulting suspension was stirred for 20 minutes at roomtemperature. A solution of the alcohol obtained at step iii (9.07 g,42.19 mmol) in 70 ml of CH₂Cl₂ was added dropwise and the reactionmixture was stirred for 20 h at room temperature. Water was added andafter separation the H₂O layer was extracted with CH₂Cl₂. The combinedorganic layers were washed with respectively 5% NaHSO₃ solution (1×) andH₂O (1×) and dried on Na₂SO₄. The drying agent was removed by filtrationand the solvent by concentration in vacuo. The residue waschromatographed (SiO₂) using CH₂Cl₂ as the eluent to give 12.9 g (94%)of the iodide Q3-I as a thick oil which crystallized on standing.Synthesis of Q7-9:

The 5-bromobenzthiophene was prepared according to: Leclerc, V.;Beaurain, N.; Pharm. Pharmacol. Commun., 6(2000)61-66.

Scheme 7-9, Step i:

Sodium metal (4.5 g, 195.9 mmol) was added in pieces to 260 ml ofabsolute EtOH. The malonic ester (116 ml, 779 mmol) was added and thereaction mixture was stirred under a nitrogen atmosphere for 30 minutes.The 5-bromobenzthiophene (29.5 g, 97.2 mmol) was added as a suspensionin 125 ml of absolute EtOH and stirring was continued at reflux for 18h. The solvent was evaporated under reduced pressure after which 250 mlH₂O and 15 g NH₄Cl were added to the residue. The aqueous layer wasextracted with CH₂Cl₂ (2×) and the combined organic layers were dried(Water Repelling Filter) and the filtrate concentrated in vacuo (bymeans of an oil pump, 8 mbar). The residue was chromatographed (SiO₂)with CH₂Cl₂/petroleumether 3/2 to give 23.9 g (64%) of the di-ester.

Scheme 7-9, Step ii:

This step was carried out analogous to step ii from Scheme 51.

Scheme 7-9, Step ii:

This step was carried out analogous to step iii from Scheme 51.

Scheme 7-9, Step iv:

This step was carried out analogous to step iii from scheme 10-12.

Scheme 7-9, Step v

This step was carried out analogous to step v from scheme 10-12.

Scheme 7-9, Step vi:

This step was carried out analogous to step iv from scheme 1-6.

Derivatives of Q7 and Q8 were prepared analogously to the abovedescribed procedures.Synthesis of Q10-12:

All reagents were commercially available. The 5-bromobenzthiophene wasprepared according to Badger et al., J. Chem. Soc., (1957) 2624, 2628.

Scheme 10-12, Step i:

To a stirred mixture of 5-bromobenzthiophene (22.5 g, 105.6 mmol) andthe acid chloride (17.4 ml, 141.3 mmol) in 135 ml benzene at 0° C.,SnCl₄ (43.1 ml, 368 mmol) was added in 2 h. Stirring was continued for 4hours at the same temperature. The reaction mixture was poured into amixture of 95 ml concentrated HCl (36-38%) in ice. The reaction mixturewas extracted with EtOAc and the organic layer was washed with H₂O (3×),1N NaOH (1×), 5% NaHCO₃ and H₂O (2×). The EtOAc fraction was dried(MgSO₄). The drying agent was removed by filtration and the solvent byevaporation under reduced pressure. The residue was recrystallized from950 ml MeOH and chromatographed with Et₂O/petroleum ether 1/1 as eluentto give 23.3 g (68%) of the acylated benzthiophene.

Scheme 10-12, Step ii:

To a stirred mixture of the acylated benzthiophene (23.3 g, 71.3 mmol)and powdered NaOH (23 g, 575 mmol) in 285 ml diethyleneglycol, hydrazinehydrate (23 ml, 474 mmol) was added. Stirring was continued for 2 hoursat 145° C. after which additional stirring for 2 hours at 180° C. wasneeded to complete the conversion. The reaction mixture was poured ontoice and acidified with concentrated HCl (36-38%). The aqueous layer wasextracted with Et₂O and the organic layer was washed with H₂O (3×) andbrine (1×) and dried (MgSO₄). The drying agent was removed by filtrationand the solvent by evaporation under reduced pressure yielded 19.7 g(93%) of the acid.

Scheme 10-12, Step iii:

At −5° C., 29 ml of thionyl chloride were added dropwise in 30 minutesto 250 ml of MeOH. The mixture was stirred for 15 minutes during whichthe temperature was kept between −10° C. and −5° C. The acid (19.7 g,65.9 mmol) was added in one time to the cooled solution. The reactionmixture was stirred for 1 hour after which is was allowed to warm toroom temperature and stirred for an additional 20 h. The reactionmixture was concentrated in vacuo and the residue was chromatographed(SiO₂) with CH₂Cl₂ as the eluent to give 20.6 g (100%) of the methylester.

Scheme 10-12, Step iv:

A mixture of the methyl ester (20.6 g, 65.8 mmol) and zinc cyanide (4.64g, 39.5 mmol) in 85 ml of dry DMF was degassed by bubbling nitrogenthrough the solution for 1 h. Palladium tetrakis, Pd(PPh₃)₄, (3.8 g,3.29 mmol) was added under a nitrogen atmosphere and the reactionmixture was stirred for 16 hours at 90° C. The reaction mixture wasdiluted with 200 ml toluene and filtered through a pad of Hyflo. Theorganic layer was washed with 5% NaHCO₃ (2×) and brine (1×). The organiclayer was dried (MgSO₄). The drying agent was removed by filtration andthe solvent by evaporation under reduced pressure. The residue waschromatographed (SiO₂) using CH₂Cl₂/petroleum ether 3/2→CH₂Cl₂ as eluentto give 15.6 g (92%) of the 5-cyanobenzthiophene.

Scheme 10-12, Step v:

To a stirring solution of the 5-cyanobenzthiophene (15.6 g, 60.2 mmol)in 250 ml 96% EtOH at 15° C. was added sodium borohydride (22.8 g, 602mmol) in one time. The reaction mixture was stirred at room temperaturefor 48 h. H₂O was added and the aqueous layer was extracted with Et₂O(3×). The combined organic layers were washed with brine (1×). The Et₂Ofraction was dried (MgSO₄). The drying agent was removed by filtrationand the solvent by evaporation under reduced pressure. The residue waschromatographed (SiO₂) with Et₂O/CH₂Cl₂ 1/9 as eluent to give 9.2 g(66%) of the alcohol Q12-OH.

Scheme 10-12, Step vi:

Was prepared according to the procedure described in Scheme 1-6, Stepiii.

Q10-OH and Q11-OH were prepared similarly using steps i, ii, iii and vrespectively.Synthesis of Q13-20:

All starting materials were commercially available.

Scheme 13-20 Step i:

To a stirring solution of 3-nitro-p-tolunitrile (16.58 g, 102.3 mmol) in55 ml DMF was added DMF-dimethylacetale (15.24 g, 128.1 mmol). Thereaction mixture turned dark red and was stirred at 110° C. for 3 h. Thesolvent was removed under reduced pressure and taken up in a mixture of300 ml EtOH and 300 ml acetic acid. The reaction mixture was heated to60° C. and iron powder (33 g, 594 mmol) was added in portions. Thereaction mixture was refluxed for 2 hours and filtered over a pad ofHyflo. Et₂O was added to the filtrate and the acidic layer was extractedwith Et₂O (1×). The Et₂O fraction was concentrated in vacuo. The residuewas chromatographed (SiO₂) with CH₂Cl₂ as the eluent to give 7.02 g(48%) of a solid, containing the 6-cyano-indole.

Scheme 13-20 Step ii:

To a stirring suspension of NaH (60%) (1.13 g, 25.96 mmol) in 60 ml DMFunder a nitrogen atmosphere was added 6-cyanoindole of step i (3.51 g,24.72 mmol) in portions. After stirring at room temperature for 1 hourthe 1-(dimethyl-tert.butylsilyl)-3-bromo propane (6.30 ml, 27.29 mmol)was added dropwise at −5° C. The reaction mixture is stirred at roomtemperature for 20 h. 400 ml H₂O and 400 ml Et₂O were added. The Et₂Olayer was separated and the aqueous layer was extracted 1× with Et₂O.The combined Et₂O layers were concentrated in vacuo. The residue waschromatographed (SiO₂) with CH₂Cl₂/petroleum ether 3/1 as the eluent togive 5.50 g (71%) as a light yellow oil.

Scheme 13-20 Step iii:

Was performed analogously to step iii in scheme 1-6, and yielded Q19-OH.

Scheme 13-20 Step iv:

The conversion of the resulting alcohols to the corresponding iododerivatives was performed analogously to the procedure described inscheme 1-6 step iv.

The 6-cyano-indole derivative Q20-OH was prepared according to theprocedure described above.

The indole, 6-Fluoroindole and 6-Chloroindole were commerciallyavailable and were further converted to the indole derivatives Q13-18-OHaccording to the procedures given above.Synthesis of Q21:

Scheme 21 Step i:

To a stirred suspension of NaH (55%) (0.48 g, 20 mmol) in 20 ml NMP atroom temperature was added dropwise a solution of benzimidazole (1.18 g,10 mmol) in 20 ml NMP. The reaction mixture turned light red andhydrogen forming was observed. After stirring at room temperature for 30minutes 3-chlorobromopropane (1.08 ml, 11 mmol) in 10 ml NMP was addeddropwise. The reaction mixture was stirred at room temperature for 2hours after which the reaction mixture was heated at 100° C. for 2 h.After additional stirring at room temperature for 72 h, H₂O and EtOAcwere added. The layers were separated and the aqueous layer wasextracted with EtOAc (2×). The combined organic layers were washed withbrine (1×) and dried (MgSO₄). The drying agent was removed by filtrationand the solvent by evaporation under reduced pressure to give 2.9 g ofQ21-Cl (150%, still NMP present) as an oil. This was used in couplingreactions with amines.Synthesis of Q22-23:

All reagents were commercially available.

Scheme 22-23 Step i:

To a stirring solution of 2,4-difluoronitrobenzene (8 g, 50.3 mmol) in100 ml CH₃CN was added 4-aminobutanol (5.61 ml, 60.4 mmol) and DIPEA(20.9 ml, 120.7 mmol). The reaction mixture was stirred at roomtemperature for 72 h. The solvent was evaporated under reduced pressureand CH₂Cl₂ was added to the residue. The CH₂Cl₂ fraction was washed withH₂O (2×), dried (by a Water Repelling Filter) and the filtrateevaporated under reduced pressure. The residue was chromatographed(SiO₂) with Et₂O as the eluent to give 9.68 g (84%) of theamino-alkylated product.

Scheme 22-23 Step ii:

To a solution of the amino-alkylated product (from step i) (9.68 g, 42.5mmol) in 250 ml EtOH (96%) was added 1 g 10% Pd/C after which themixture was hydrogenated at room temperature (1 atm) for 3 h. Thereaction mixture was filtered through a pad of Hyflo and the blackfiltrate was concentrated in vacuo under reduced pressure to give 8.42 g(100%) of the corresponding aniline.

Scheme 22-23 Step iii:

A mixture of the aniline (from step ii) (8.42 g, 42.5 mmol) in 25 mlformic acid (96%) was refluxed for 2.5 hours after which it was allowedto cool to room temperature. H₂O was added and after cooling, to thereaction mixture 50 ml of 50% NaOH was added. After stirring for 2 hoursthe aqueous layer was extracted with CH₂Cl₂. The CH₂Cl₂ fraction wasdried (by a Water Repelling Filter) and concentrated in vacuo underreduced pressure. The residue was chromatographed (SiO₂) withCH₂Cl₂/MeOH 9:1 as the eluent to give 8.1 g (92%) of the benzimidazole.

Scheme 22-23 Step iv:

The conversion of the resulting alcohols to the corresponding iododerivatives was performed according to the procedure described in scheme1-6 step iv. In this case triphenylphosphine on solid support was used.

Q22-OH was prepared via the same procedure as described above.Synthesis of Q24:

All reagents were commercially available.

Scheme 24 Step i:

A suspension of sodium borate tetrahydrate (32.5 g, 211.2 mmol) in 195ml of acetic acid was heated until the temperature of the reactionmixture was above 50° C. The reaction temperature was kept this waywhile 2-chloro-4-cyanoaniline (5.93 g, 38.9 mmol) was added in portionsover 1 h. Stirring and heating were continued for 2 hours on an oil bathof 62° C. After cooling to room temperature the reaction mixture waspoured into 1 L icewater. The aqueous layer was extracted with Et₂O(3×). The combined organic layers were washed with H₂O (2×) and dried(MgSO₄). The drying agent was removed by filtration and the solvent byevaporation under reduced pressure. The residue was chromatographed(SiO₂) with Et₂O/petroleum ether 1/3 as eluent to give 5.27 g (74%) ofthe oxidized product.

Scheme 24 Step ii:

To a stirring solution of 2-chloro-4-cyanonitrobenzene from step i (2.48g, 13.6 mmol) in 12 ml DMF was cooled in ice. 4-aminobutanol (5.50 ml,59.3 mmol) was added and the reaction mixture was slowly allowed to warmto room temperature after which stirring was continued at roomtemperature for 72 h. H₂O was added and the aqueous layer was extractedwith CH₂Cl₂ (2×) The combined organic layers were washed with H₂O (3×),dried (by a Water Repelling Filter) and evaporated under reducedpressure. The residue was chromatographed with Et₂O/petroleum ether 4:1as eluent to give 2.6 g (49%) of the amino-alkylated product.

Scheme 24 Step iii:

Prepared according to step ii, in scheme 22-23.

Scheme 24 Step iv:

Prepared according step iii, in scheme 22-23.

Scheme 24 Step v:

Prepared according step iv, in scheme 22-23.Synthesis of Q25-28:

All reagents were commercially available.

Scheme 25-28 Step i:

To a stirring solution of 3-nitro-p-tolunitrile (8.1 g, 50 mmol) in 30ml DMF was added DMF-dimethylacetale (13.3 ml, 100 mmol) and thereaction mixture was stirred at 120° C. for 3 h. The solvent wasevaporated under reduced pressure and the residue was taken up inCH₂Cl₂. The CH₂Cl₂ fraction was washed with H₂O (2×), dried (by a WaterRepelling Filter). The drying agent was removed by filtration and thesolvent by evaporation under reduced pressure to give 10.6 g (98%) ofthe adduct.

Scheme 25-28 Step ii:

To a stirring emulsion of the adduct (from step i) (6 g, 27.6 mmol) in175 ml Et₂O was added 8.1 g NH₄Cl and 29 g zinc granules (40 mesh).After stirring at room temperature for 2 hours 100 ml THF was added todissolve the starting material. After an additional stirring for 6 hoursthe reaction mixture was filtered over a pad of Hyflo. Half of theresulting filtrate was used in the next step.

Scheme 25-28 Step iii:

To the filtrate of the former step ii was added 2-bromoethanol (7.9 ml,112 mmol), Aliquat (0.6 g, 10 mol %) and 90 ml 10% NaOH. The reactionmixture was stirred at room temperature for 20 h. After separation ofthe layers, the aqueous layer was extracted with Et₂O (1×). The combinedorganic layers were washed with H₂O (4×) and dried (MgSO₄). The dryingagent was removed by filtration and the solvent by evaporation underreduced pressure (by means of an oil pump). The residue waschromatographed (SiO₂, eluent: CH₂Cl₂ 4 CH₂Cl₂/Et₂O 4:1) to give 1 g(36%) of the corresponding alcohol Q27-OH.

Scheme 25-28 Step iv:

The conversion of the resulting alcohols to the corresponding iododerivatives was performed according to the procedure described in scheme1-6 step iv.

Q25-OH, Q26-OH and Q28-OH were prepared analogously to the proceduredescribed above.Synthesis of Q29:

The naphtylpropylalcohol was prepared according to: Searles, J. Amer.Chem. Soc., 73 (1951) 124.

Scheme 29 Step i:

The conversion of the resulting alcohol to the corresponding iododerivative was performed according to the procedure described in scheme1-6 step iv.Synthesis of Q30:

2-chloro-7-iodo-naphtalene was prepared according to the literature(Beattie; Whitmore; J. Chem. Soc. 1934, 50, 51, 52)

Scheme 30 Step i:

A 100 ml roundbottom flask under an nitrogen atmosphere was charged with2-chloro-7-iodo-napthalene (11 mmol, 3.60 g), allyl-tributyltin (13mmol, 4.30 g, 3.96 ml), tetrakis(triphenylphosphine)palladium(0) (0.55mmol, 0.635 g) and 10 ml degassed benzene. The mixture was heated torelfux under a nitrogen atmosphere and after 20 hours another portion oftetrakis(triphenylphosphine)palladium(0) (0.55 mmol, 0.635 g) was added.The mixture was again heated at reflux for 20 hours after which it wasallowed to cool to room temperature after which it was poured into 70 mlof a 10% KF-solution. After 30 min stirring at room temperature thesuspension was filtered over Hyflo Supercel®. The filtrate was washedwith water, brine and dried (Na₂SO₄). Column chromatography on silicagel (eluens 1/9 toluene/petroleum ether) afforded almost pure2-allyl-7-chloro-napthalene (1.80 g, 80%).

Scheme 30 Step ii:

A 100 ml threeneck roundbottom flask under a nitrogen atmosphere wascharged with 2-allyl-7-chloro-napthalene (1.80 g, 8.9 mmol) and 12 ml ofdry THF. The mixture was cooled in an ice-bath and borane-THF (3.05mmol, 3.05 ml 1.0 M borane in THF) was added dropwise in about 20minutes After the addition the mixture was allowed to warm to roomtemperature and stirred for 20 hours. 3.0 N NaOH solution (2.65 mmol,0.89 ml) was then added to the solution and the mixture was cooled in awaterbath while adding 30% hydrogen peroxide (10.62 mmol, 1.1 ml)dropwise at such a rate that the temperature did not exceed 30° C. Afterthe addition the mixture was stirred for 6 hours at room temperature.

Water and diethyl ether were added and the organic layer was separated.The water layer was extracted again with ethyl ether and the combinedorganic extracts were washed with water, brine and dried (Na₂SO₄). Thedrying agent was removed by filtration and the solvent by evaporation invacua. Flash column chromatography on silica gel (eluent: 1/99methanol/dichloromethane) afforded3-(7-chloro-napthalene-2-yl)-propan-1-ol (0.79 g, 40%) Q30-OH.

Scheme 30 Step iii:

The conversion of the resulting alcohol to the corresponding iododerivative was performed according to the procedure described in scheme79-84 step iii, yielding Q30-I.Synthesis of Q31:

The fluorobromonaphtalene was prepared according to: Adcock, W. et al.,Aust. J. Chem., 23 (1970)1921-1937.

Scheme 31 Step i:

To a stirred suspension of magnesium turnings (0.49 g, 20 mmol) and 0.1ml 1,2-dibromoethane in 20 ml THF was added the fluoronaphtalene (0.45g, 2 mmol) in one time. After the start of the grignard a solution ofthe fluoronaphtalene (4.06 g, 18 mmol) in 25 ml THF was slowly addeddropwise. The temperature rose during the addition to 40° C. Thereaction mixture was stirred at room temperature for 2 hours until allthe magnesium had disappeared. A freshly prepared solution from LiCl andCuCN in THF was added dropwise at −10° C. which resulted in a dark greensolution. At the same temperature was added dropwise a solution of allylbromide (1.9 ml, 22 mmol) in 15 ml THF. After the complete addition thereaction mixture was stirred at −10-0° C. for 30 minutes. The greencolor disappeared and stirring was continued at room temperature for 20h. The reaction mixture was poured into 200 ml of saturated NH₄Cl andextracted with CH₂Cl₂ (3×). The combined organic layers were washed withbrine and dried (MgSO₄). The drying agent was removed by filtration andthe solvent by evaporation under reduced pressure. The residue waschromatographed (SiO₂) using petroleum ether as eluent to give 1.65 g(44%) of the corresponding allylfluoro-naphtalene.

Scheme 31 Step ii:

To a cooled stirring solution of the allyl-fluoronaphtalene (1.65 g, 8.8mmol) in 10 ml THF at −5° C. was slowly added dropwise 3.05 ml 1.0 MBorane.THF-complex. After stirring for 20 minutes at the sametemperature and additional stirring at room temperature iodine (2.11 g,8.6 mmol) was added in one time. 3.1 ml of a freshly prepared 2.7 Msolution of sodium metal in MeOH) was slowly added dropwise (exothermic)after which the reaction mixture is stirred at room temperature for 20h. 75 ml NaHSO₃ was added and the aqueous layer was extracted withCH₂Cl₂ (3×). The organic layer was washed with brine (1×) and dried(MgSO₄). The drying agent was removed by filtration and the solvent byevaporation under reduced pressure. The residue was chromatographed(SiO₂) using petroleum ether as eluent to give 1.25 g (46%) of theiodide Q31-I as a white solid.Synthesis of Q32-39, Q41-42:

Scheme 32-39, 41-42 Step i:

A mixture of KOH pellets (140 g, 2.5 mol) and 10 ml H₂O in a nickelcrucible was heated to 250° C. with a Bunsen burner while being stirredwith a stainless steel stirrer. The flame is removed and7-amino-2-naphtalenesulfonic acid sodium salt (0.245 mol, 60.0 g) wasadded to the clear liquid in 3 portions. The clear liquid changes into athick black slurry which is again strongly heated with a Bunsen burner.At about 280° C. gas evolved and the temperature of the mixture quicklyrises to 310-320° C. This temperature was maintained for 8 minutes afterwhich the mixture was allowed to cool to about 200° C. The thick blackpaste was carefully transferred to a 3 litre beaker filled with ice. Theproduct of 2 runs were combined and neutralized with concentrated HClunder cooling with an ice-salt bath. The suspension wa filtered and theblack solid wa washed with 4 500 ml portions of 1.0 N HCl and discarded.The brown, clear filtrate that is obtained was cooled in an ice-saltbath and KOH-pellets are added until a light suspension was obtained.After addition of a saturated NH₄OAc-solution the green-grey solid fullyprecipitates and was collected through filtration to obtain7-amino-naphtalene-2-ol (27.9 g, 36%) after drying in the air.

Scheme 32-39, 41-42 Step ii:

7-amino-naphtalene-2-ol (0.169 mol, 27.0 g) is suspended in 750 ml DCMand TEA (0.169 mol, 17.2 g, 23.6 ml) was added. The mixture wais stirredfor 30 min at room temperature after which it was cooled to −5° C. in anice-salt bath. A solution of p-Tosylchloride (0.17 mol, 32.4 g) in 250ml DCM was added over a period of 2.5 hours at −5-0° C. The mixture wasstirred for 10 minutes at −5-0° C. after which it was allowed to warm toroom temperature and stirred for 18 hours. 1 L of H₂O was added to themixture and the resulting suspension was filtered over Hyflo Super Cel®and the filtrate was transferred to a separatory funnel. Afterextracting the organic layer, the water-layer was again extracted withDCM (2×). The combined organic layers are washed with brine, dried(Na₂SO₄) and concentrated in vacuo to give 51.5 g of a black oil whichwas purified by column chromatography on silica gel (eluens 1/1ethylacetate/petroleum ether) to afford toluene-4-sulfonicacid-7-amino-napthalene-2-yl-ester (12.1 g, 23%).

Scheme 32-39, 41-42 Step iii:

A 500 ml threeneck roundbottom flask made from PFA was charged with 100g Pyridine/HF complex (30:70% w/w) and cooled to −10° C. with anice/EtOH bath toluene-4-sulfonic acid-7-amino-napthalene-2-yl-ester(38.6 mmol, 12.1 g) was added in one portion and the mixture was stirredfor 10 minutes after which a clear purple solution was obtained. Thissolution was cooled to <−30° C. in an dry-ice cooling bath and sodiumnitrite (42.5 mmol, 2.93 g, dried by heating at 140° C. for 3 days) wasadded in one portion. The dry-ice bath was replaced by a normal ice-bathand the mixture was stirred at 0° C. for 20 minutes after which it washeated to 55-60° C. on an oilbath (evolution of nitrogen was observed).After 1.5 hours nitrogen evolution ceased and the mixture was allowed tocool to room temperature and poured into a large beaker filled with ice.The mixture was transferred to a separatory funnel and extracted 3 timeswith DCM. The organic layers where pooled together, washed with brineand dried (Na₂SO₄). Concentration in vacuo afforded 10.4 g of a red oilwhich was purified by flash column chromatography on silica gel (eluens1/4 ethylacetate/petroleum ether) to give toluene-4-sulfonicacid-7-fluoro-napthalene-2-yl-ester (7.1 g, 58%)

Scheme 32-39, 41-42 Step iv:

A 500 ml roundbottom flask protected with a CaCl₂-tube was charged withtoluene-4-sulfonic acid-7-fluoro-napthalene-2-yl-ester (22.4 mmol, 7.1g) and 200 MeOH. The suspension was heated until a clear solution wasobtained and then cooled down to room temperature in a waterbad toafford a fine suspension. Magnesium (179 mmol, 4.36 g) was added to themixture which was then stirred for 4 hours at room temperature. Thebrown suspension was cooled in an ice-EtOH bath and acidified with 6NHCl and then concentrated in vacua. The mixture was transferred to aseparatory funnel and extracted 3 times with ethylether. The organicextracts are pooled together, washed with brine and dried (Na₂SO₄). Thedrying agent was removed by filtration and the solvent by evaporation invacua. Flash column chromatography on silica gel (eluensdichloromethaan) afforded unpure 7-fluoro-napthalene-2-ol (4.69 g) as anoff white solid. This solid was dissolved in DCM and extracting 3 timeswith 2N NaOH-solution. The basic extracts were combined and acidifiedwith 3N HCl while cooling with an ice bath. White crystals precipitatedfrom the solution and were collected by filtration and dried in the airto afford pure 7-fluoro-napthalene-2-ol. (3.16 g, 87%)

Scheme 38-45: 47-48, Step v:

To a stirred suspension at −5° C. 0.97 g (6 mmol) of2-hydroxy-7-fluoronaphtalene, 2.83 g (10.8 mmol) of triphenylphosphineand 1.11 ml (12.6 mmol) of 3-bromo-1-propanol in 30 ml of toluene, wasadded dropwise a solution of 2.13 ml (10.8 mmol) DIAD in 5 ml toluene.The reaction mixture was allowed to reach room temperature after whichstirring was continued overnight. The reaction mixture was concentratedin vacuo and the residue taken up in 30 ml of diethylether. The mixturewas filtered an the filtrate concentrated in vacuo and the residuesubjected to flash column chromatography (SiO2, eluent: CH₂Cl₂/petroleumether 1/5). Yield 1.28 g (75%) of Q37-Br.

Q32 was synthesized as Q32-I, Q33-36, Q38-39 and Q41-42 derivatives wereprepared similarly to the above described procedures (as bromides).Synthesis of Q40, Q43:

Scheme 40, 43 Step i:

A mixture of 7-fluoro-2-naphtol (see Scheme 32-39, 41-42 step iv) (0.62g, 3.82 mmol), the alkene (1.11 ml, 9.56 mmol) and K₂CO₃ (1.58 g, 11.5mmol) in 35 ml CH₃CN was refluxed for 3 hours after which was was cooledto room temperature and evaporated under reduced pressure. The residuewas taken up in H₂O and Et₂O and extracted with Et₂O (2×). The combinedorganic layers were washed with H₂O (1×) and brine (1×) after which itwas dried (Na₂SO₄). The drying agent was removed by filtration and thesolvent by evaporation under reduced pressure. The residue waschromatographed (SiO₂) with CH₂Cl₂/petroleum ether 1/5 as eluent to give0.56 g (58%) of the fluoronaphthol derivative Q43-Cl as a colorless oil.Synthesis of Q44:

Scheme 44 Step i:

For the fluornaphtol, see Scheme 32-39, 41-42 step iv. This Mitsunobureaction was performed analogously to step v in scheme 32-39, 41-42.

Scheme 44 Step ii:

This step can be performed similar to step iii in scheme 1-6, andyielded Q44-OH.

Scheme 44 Step iii:

Q44-OH was oxidized following the procedure of step i in scheme B2. Theproduct, Q′44-C═O was used in the reductive alkylation of amines.Synthesis of Q45-50:

The starting acid and reagents were commercially available. TheCl-C4-MgBr was prepared according to: C. R. Hebd, Seances Acad. Ser. C,268 (1969)1152-1154.

Scheme 45-50 Step i:

To a solution of the acid (25 g, 148.8 mmol) in 140 ml benzene was added0.07 ml DMF after which oxalylchloride was added all at once. Immediatefoaming of the reaction mixture was observed. The reaction mixture wasstirred for at room temperature 18 hours and the solvent was removed byevaporation under reduced pressure. Acetonitrile was added to theresidue for co-evaporation and again removed by evaporation underreduced pressure to give 27.75 g (100%).

Scheme 45-50 Step ii:

AlCl₃ (27.8 g, 208 mmol) was suspended in 200 ml 1,2-dichloroethane. Themixture was cooled under a nitrogen atmosphere to 0-5° C. and a solutionof the acid chloride (27.75 g, 148.8 mmol) in 140 ml 1,2-dichloroethanewas added dropwise in 1 h. The cooling bath was removed and afterstirring for 30 min., stirring was continued for 2 hours at 70° C. Aftercooling to room temperature the reaction mixture was poured into amixture of ice and 330 ml concentrated HCl (36-38%). The aqueous layerwas extracted with CH₂Cl₂ and the resulting organic layer was washedwith H₂O (2×), 5% NaHCO₃ and brine. The organic layer was dried (MgSO₄).The drying agent was removed by filtration and the solvent byevaporation under reduced pressure to give 19.02 g (85%).

Scheme 45-50 Step iii:

To a cooled solution of 0.5M cyclopropyl magnesiumbromide in THF (100ml, 50 mmol) at 15° C. was added a solution of the ketone (5.3 g, 35.3mmol) in 40 ml THF. The reaction mixture was stirred at reflux for 2hours after which was was cooled in an ice bath. 50 ml saturated NH₄Clwas added dropwise and the aqueous layer was extracted with Et₂O. TheEt₂O was washed with brine (1×), dried (MgSO₄) and evaporated underreduced pressure. The residue was dissolved in 85 ml acetic acid and 62ml of a 20% HBr solution was added. The reaction mixture was stirred for20 h. H₂O was added and the aqueous layer was extracted with CH₂Cl₂. Theorganic layer was further washed with H₂O (1×) and 5% NaHCO₃ (1×). Theorganic layer was dried (by a Water Repelling Filter) and evaporatedunder reduced pressure. The residue was chromatographed withCH₂Cl₂/petroleum ether 2.5/97.5 as eluent to give 4.44 g (49%) of theindene Q49-Br.

Scheme 45-50 Step iv:

Was prepared according to the procedure as described for step iii,yielding Q50-Cl Q45, Q46, Q47, and Q48 derivatives were made analogouslyto the above described procedure.Synthesis of Q51:

The starting materials were commercially available.

Scheme 51 Step i:

A mixture of the Grignard reagent (90 ml, 90 mmol) and CuI (18 mg, 0.02mmol) was stirred for 15 minutes after which it was cooled in an icebath. A solution of the di-ester (18.9 ml, 96.7 mmol) in 25 ml THF wasadded in 90 min and the reaction mixture was, stirred at 0° C. for 2 h.100 ml saturated NH₄Cl was added dropwise and the aqueous layer wasextracted with Et₂O. The Et₂O fraction was washed with brine (1×) anddried (MgSO₄). The drying agent was removed by filtration and thesolvent by evaporation under reduced pressure. The residue waschromatographed with CH₂Cl₂/petroleum ether 1/1 as eluent to give 26.17g (98%) of the adduct.

Scheme 51 Step ii:

To a stirring solution of the adduct (26.17 g, 88.4 mmol) in 222 ml EtOHwas added 265 ml 10% NaOH. The reaction mixture was refluxed for 3 hoursand the solvent was evaporated under reduced pressure. The residue wascooled in ice and acidified with concentrated HCl (36-38%). The aqueouslayer was extracted with EtOAc. The EtOAc fraction was washed with brine(1×) and dried (MgSO₄). The drying agent was removed by filtration andthe solvent by evaporation under reduced pressure to give 20.9 g (99%)of the di-acid.

Scheme 51 Step iii:

A mixture of the di-acid (20.9 g, 87.1 mmol) and Cu₂O (0.62 g, 4.34mmol) in 600 ml CH₃CN was refluxed for 16 h. The solvent was removed byevaporation under reduced pressure and 125 ml 3N HCl was added to theresidue. The aqueous layer was extracted with EtOAc. The EtOAc fractionwas washed with brine (1×) and dried (MgSO₄). The drying agent wasremoved by filtration and the solvent by evaporation under reducedpressure to give 16.9 g (99%) of the de-carboxylated product.

Scheme 51 Step iv:

Was prepared according to step i in scheme 45-50.

Scheme 51 Step v:

Was prepared according to step ii in scheme 45-50.

Scheme 51 Step vi:

Was prepared according to step iii in scheme 45-50, yielding Q51-Cl.Synthesis of Q52-53:

Scheme 52-53 Step i:

A 3 litre beaker was charged with 2-amino-5-fluoro-benzoic acid (64mmol, 10 g), 100 ml H₂O and 110 ml concentrated HCl and the suspensionwas cooled to 0° C. in an ice/aceton bath. A solution of natrium nitrite(64 mmol, 4.44 g) in 68 ml H₂O was added dropwise to the mixture whilethe temperature was maintained at below 3° C. After the addition wascomplete the brown solution was added in portions over 20 minutes, undera stream of sulfurdioxide, to a solution of 760 ml H₂O saturated withsulfurdioxide cooled at 0-5° C. with an ice-bath. After the addition wascomplete the ice-bath was removed and the solution was allowed to warmto room temperature while the stream of sulfurdioxide was maintained.After 1 hour the supply of sulfurdioxide was discontinued and thesolution was allowed to stand at room temperature overnight. To the darkyellow solution which was obtained was added 620 ml concentrated HCl andafter cooling the mixture a yellow precipitate separates which wascollected on a cooled buchner funnel. The solid was suspended in asolution of 2 ml concentrated HCl and 200 ml H₂O and the mixture washeated to reflux. After a time the solid dissolves and a clear solutionwas obtained. After 1.5 hours of reflux a orange/brown solid hascrystallized and the mixture was allowed to cool to room temperature andwas concentrated to about 50 ml in vacuo. The solid was collected anddried in the air to afford 5-fluoro-1,2-dihydro-indazol-3-one (5.05 g,52%)

Scheme 52-53 Step ii:

5-fluoro-1,2-dihydro-indazol-3-one (32 mmol 5.05 g) was suspended in 30ml pyridine and under cooling with an ice-bath chloroethylformiate (64mmol, 6.94 g, 6.09 ml) was, added dropwise. The mixture was heated toreflux for 3 hours and was then allowed to cool to room temperature adconcentrated in vacuo to afford a dark red oil which crystallizes afterthe addition of water. The solid was filtered and dried in the air toafford the corresponding urethane (5.52 g, 77%)

Scheme 52-53 Step iii:

To 20 ml toluene under a nitrogen atmosphere was added the urethanederivative (from step ii) (0.45 g, 2 mmol), 3-bromopropanol (0.18 ml,2.1 mmol), Bu₃P (0.40 g, 2 mmol) and ADDP (0.5 g, 2 mmol). After theaddition of ADDP the solution turned clear. The reaction mixture washeated at 85° C. for 20 hours and cooled to room temperature. 2N NaOHand EtOAc were added and the aqueous layer was extracted with EtOAc(2×). The combined organic layers were washed with 2N NaOH (1×), H₂O(1×) and brine (1×) after which the EtOAc was dried (Na₂SO₄) andevaporated under reduced pressure. The residue was chromatographed withCH₂Cl₂/MeOH 99:1 as eluent to give 0.22 g (32%) of the alkylatedindazol-3-one.

Scheme 52-53 Step iv:

Was performed according to the procedure as described in scheme A2, Stepi.

Scheme 52-53 Step v:

A mixture of the ethyl carbamate (0.38 g, 0.79 mmol) and K₂CO₃ (0.38 g,2.74 mmol) in 21 ml of MeOH/DME/H₂O (5/1/1) was stirred at roomtemperature for 4 h. The reaction mixture was further purified using aSCX-column (ion exchange column) with 1N NH₃/MeOH as eluent to rinse theproduct off the column. The eluate was evaporated under reduced pressureand the residue refluxed in 20 ml CH₃CN. The suspension was filtered bysuction to give 0.28 g (86%) of the de-protected product as a lightorange solid containing compound 125 which was later transformed intoits mono HCl salt (AcCl/MeOH), 125-HCl.

The Q53 analogue can be synthesized as well, as described above.

Compounds 48, 49 and 124 were prepared analogously to the proceduresgiven above.Synthesis of Q54-59:

The indazoles were preapared according to Christoph Rüchardt, VolkertHassemann; Liebigs Ann. Chem.; (1980) 908-927.

Scheme 54-59, Step i:

56; R=Cl, n=3:

NaH (55%) (2.14 g, 49.15 mmol) was suspended in 70 ml of dry DMF under aN₂ atmosphere. 6-chloro-indazole (7.5 g, 49.15 mmol) was added at roomtemperature. The mixture was stirred for 1 hour before cooling with anice bath and (3-bromo-propoxy)-tert-butyl-dimethyl-silane (11.4 ml,49.15 mmol) was added dropwise. After stirring for an additional 15minutes the mixture was allowed to reach room temperature, stirring wascontinued for another 8 hours. Subsequently, the mixture wasconcentrated in vacuo and the residue was dissolved in DCM, the organiclayer was then washed with water (3×). The organic layer wasconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (SiO₂, eluent: petroleum ether/diethylether 5/1 ? 4/1) to afford the N1 substituted indazole in 61% yield.

Scheme 54-59, Step ii:

To a stirred solution of KF.2H₂O (4.3 g, 45.24 mmol) and benzyltri-ethyl ammonium chloride (7.6 g, 33.18 mmol) in 300 ml acetonitrile,the N1 substituted indazole (from step i) (9.8 g, 30.16 mmol) was added.The mixture was warmed to reflux and stirred for 8 hours. The solventwas evaporated and DCM was added to the residue. The organic layer waswashed with water (3×). De organic layer was concentrated in vacuo. Thecrude product was purified by flash chromatography on silica (eluent:diethylether→1% MeOH in diethylether) to afford the3-(indazol-1-yl)-propanol in 95% yield.

The other indazolyl alcohols were prepared analogously. In step ii,tetrabutyl ammonium chloride in THF can be used instead of thecombination KF.2H₂O/benzyl tri-ethyl ammonium chloride.

Synthesis of Q60:

Q60-Br was synthesized analogously to the synthesis depicted in Scheme52-53, using bromoethanol in the Mitsunobu step iii.

Synthesis of Q61-62:

Q61-1 and Q62-1 were synthesized analogously to the synthesis depictedin scheme 13-20, Steps ii, iii and iv.

Synthesis of Q63:

Q63-1 was synthesized as depicted in scheme 63:

Scheme 63, Step i:

Through a suspension containing the fluorobromonapthalene (0.90 g, 4mmol), tri-phenylphospine (0.21 g, 0.8 mmol),dichlorobis(tri-phenylphospine)palladium (0.28 g, 0.4 mmol) in 15 mlEt₃N, nitrogen was bubbled for 1 hour. 3-Butyn-1-ol (0.4 g, 0.45 ml, 6mmol) was added and the mixture was heated to 40-50° C. on an oilbath.After 15 minutes of stirring at this temperature, CuI (0.15 g, 0.8 mmol)was added and the mixture was heated at 70° C. and stirred for 48 hours.

The resulting black suspension was allowed to reach room temperature anddiethyl ether and water were added. The fractions were separated and thewater layer was extracted twice with diethyl ether. The combined organicextracts were washed with water, brine and dried (Na₂SO₄). After removalof the drying agent by filtration and solvent by concentration in vacuo,the residue was subjected to flash chromatography (SiO₂, eluent: DCM)affording Q63-OH, 4-(2-fluoro-napthalene-7-yl)-3-butyne-1-ol (0.30 g,1.46 mmol).

Scheme 63, Step ii:

The conversion of the alcohol of step i to the correspondingiodo-derivative was performed according to scheme 1-6 step iv, yieldingQ63-1.Synthesis of Q64:

Scheme 64, Step i:

A solution of Red-Al (4.47 ml of a 3.4 M solution in toluene) in 25 mlof dry diethyl ether was cooled in an ice-bath under nitrogen to which asolution of Q63-OH (1.90 g, 9.5 mmol) in 40 ml of diethylther (dry) wasadded dropwise. After the addition was complete, the resulting mixtureis stirred for 10 min at 0° C. after which it was allowed to reach roomtemperature and stirred for an additional 2.5 hours. The reactionmixture was again cooled in a ice-bath and quenched by the carefuladdition of 50 ml of 3.6 M H₂SO₄. The reaction mixture was extractedthree times with diethyl ether. The combined organic extracts are washedwith water, brine, and dried Na₂SO₄). After removal of the drying agentby filtration and solvent by concentration in vacuo, the residue wassubjected to flash chromatography (SiO₂, eluent: DCM) affording 1.17 gof Q64-OH, 4-(2-fluoro-naphtalene-7-yl)-3-butene-1-ol (5.8 mmol).

Scheme 64, Step ii:

5 ml of concentrated hydrochloric acid is added to a solution of Q64-OH(1.17 g, 5.8 mmol) in 5 ml of THF. The mixture is stirred for 4.5 hoursat room temperature after which another 2 ml of concentratedhydrochloric acid and 2 ml of THF are added. After another 30 minutesdiethyl ether and water are added and the resulting fractions wereseparated. The water layer is extracted twice with diethyl ether. Thecombined organic fractions are washed with water, brine, dried (Na₂SO₄).After removal of the drying agent by filtration and solvent byconcentration in vacuo, the residue was subjected to flashchromatography (SiO₂, eluent: DCM) affording 1.03 g of Q64-Cl (4.67mmol).

The specific compounds of which the synthesis is described above areintended to further illustrate the invention in more detail, andtherefore are not deemed to restrict the scope of the invention in anyway. Other embodiments of the invention will be apparent to thoseskilled in the art from consideration of the specification and practiceof the invention disclosed herein. It is thus intended that thespecification and examples be considered as exemplary only, with a truescope and spirit of the invention being indicated by the claims.ABBREVIATIONS AcCl acetylchloride ADDP 1,1′-(azodicarbonyl)dipiperidineCDI carbonyldiimidazol Dba see Huang et al., J. Am. Chem. Soc.,125(2003)6653 DCE dichloroethane DCM dichloromethane DIADdiisopropyldiazodicarboxylate DIPE diisopropylether DIPEAdiisopropylethylamine CH₂Cl₂(ml) MeOH(ml) NH₄OH(ml) DMA 0.125 980 18.751.25 DMA 0.187 970 28.13 1.87 DMA 0.25 960 37.5 2.5 DMA 0.50 920 75.05.0 DMA 0.75 880 112.5 7.5 DMA 1.00 840 150.0 10.0 DMAP4-dimethylaminopyridin DME dimethoxyethane DMF N,N-dimethylformamideEtOH ethanol MeOH methanol MTBE methyl(tert.)-butylether NMPN-methylpyrrolidon PA petroleum ether TBAB tetrabutylammoniumbromideTBAC tetrabutylammoniumchloride TBAF tetrabutylammoniumfluoride THFtetrahydrofurane XPHOS see Huang et al., J. Am. Chem. Soc.,125(2003)6653

Example Formulation of Compound 56 Used in Animal Studies

For oral (p.o.) administration: to the desired quantity (0.5-5 mg) ofthe solid compound 56 in a glass tube, some glass beads were added andthe solid was milled by vortexing for 2 minutes. After addition of 1 mlof a solution of 1% methylcellulose in water and 2% (v/v) of Poloxamer188 (Lutrol F68), the compound was suspended by vortexing for 10minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH(0.1N). Remaining particles in the suspension were further suspended byusing an ultrasonic bath.

For intraperitoneal (i.p.) administration: to the desired quantity(0.5-15 mg) of the solid compound 56 in a glass tube, some glass beadswere added and the solid was milled by vortexing for 2 minutes. Afteraddition of 1 ml of a solution of 1% methylcellulose and 5% mannitol inwater, the compound was suspended by vortexing for 10 minutes. Finallythe pH was adjusted to 7.

Example Pharmacological Test Results

TABLE 2 In vitro affinities and functional activity of compounds of theinvention Dopamine-D₂ 5-HT reuptake Dopamine-D₂ binding binding cAMPaccum compound pK_(i) pK_(i) ε (intrinsic activity) 6 7.7 9.8 0.85 7 8.28.5 0.39 8 8.3 8.9 0.10 16 8.5 9.1 0.73 53 8.8 8.8 0.62 56 8.9 8.1 0.3879 7.1 8.5 0.10 94 7.8 8.5 0.70 98 6.9 9.0 0.75 102 7.4 9.0 0.81 108 7.78.1 0.95 117 8.1 >9.0 0.29 135 7.2 8.7 0.45 140 7.0 7.3 0.24

Dopamine-D₂ and serotonin reuptake receptor affinity data obtainedaccording to the protocols given above are shown in the table below. Invitro functional activity at cloned human dopamine D_(2,L) receptors asmeasured by accumulation of radiolabeled cAMP (potency: pEC₅₀, intrinsicactivity ε)

1. Compounds of the general formula (1):

wherein X═S or O, R₁ is H, (C₁-C₆)alkyl, CF₃, CH₂CF₃, OH orO—(C₁-C₆)alkyl R₂ is H, (C₁-C₆)alkyl, halogen or cyano R₃ is H or(C₁-C₆)alkyl R₄ is H, (C₁-C₆)alkyl, optionally substituted with ahalogen atom T is a saturated or unsaturated carbon chain of 2-7 atoms,wherein one carbon atom may be replaced with a nitrogen atom optionallysubstituted with an (C₁-C₃)alkyl, CF₃ or CH₂CF₃ group, an oxygen atom ora sulphur atom, which chain is optionally substituted with one or moresubstituents selected from the group consisting of (C₁-C₃)alkyl,(C₁-C₃)alkoxy, halogen, cyano, trifluoromethyl, OCF₃, SCF₃, OCHF₂ andnitro, Ar is selected from the groups:

which Ar group is optionally further substituted with one or moresubstituents selected from the group consisting of (C₁-C₃)alkyl,(C₁-C₃)alkoxy, halogen, cyano, trifluoromethyl, OCF₃, SCF₃ OCHF₂ andnitro, and in which Ar groups that contain a five-membered ring, thedouble bond in the five-membered ring may be saturated, and tautomers,stereoisomers and N-oxides thereof, as well as pharmacologicallyacceptable salts, hydrates and solvates of said compounds of formula (1)and its tautomers, stereoisomers and N-oxides.
 2. Compounds of theformula (1) as claimed in claim 1, wherein the phenylpiperazine part ofthe molecule is selected from the group consisting of:

in which formulae the dot represents the attachment to ‘T’ of formula(1), and wherein the second part of the molecule, represented by thesymbols -T-Ar in formula (1), is selected from the group consisting of:

in which formulae the dot represents the attachment to thephenylpiperazine part of the compounds of formula (1). and tautomers,stereoisomers and N-oxides thereof, as well as pharmacologicallyacceptable salts, hydrates and solvates of said compounds of formula (1)and its tautomers, stereoisomers and N-oxides.
 3. A pharmaceuticalcomposition comprising, in addition to a pharmaceutically acceptablecarrier and/or at least one pharmaceutically acceptable auxiliarysubstance, a pharmacologically active amount of at least one compound ofclaim 1, or a salt thereof, as an active ingredient.
 4. A method ofpreparing a composition as claimed in claim 3, characterised in that atleast one compound of claims 1 or a salt thereof, is brought into a formsuitable for administration
 5. A compound as claimed in claim 1, or asalt thereof, for use as a medicament.
 6. Use of a compound as claimedin claim 1 for the preparation of a pharmaceutical composition for thetreatment of CNS disorders.
 7. Use as claimed in claim 6, characterizedin that said disorders are aggression, anxiety disorders, autism,vertigo, depression, disturbances of cognition or memory, Parkinson'sdisease, schizophrenia and other psychotic disorders.
 8. Use as claimedin claim 6, characterized in that said disorder is depression.
 9. Use asclaimed in claim 6, characterized in that said disorders areschizophrenia and other psychotic disorders.
 10. Use as claimed in claim6, characterized in that said disorder is Parkinson's disease.